DESCRIPTION (adapted from the application) Up to 3% of the world population is infected with hepatitis C virus (HCV), a hepatotropic RNA virus that causes acute and chronic hepatitis as well as cirrhosis and hepatocellular carcinoma. HCV infection results in chronicity in most cases (85%) despite the presence of antiviral immune response. While the basis for high rate of persistent infection is not well defined, the role of cellular immunity in the outcome of HCV infection can be directly examined by comparing patients with HCV clearance, persistence and resistance The central hypothesis in this application is that viral clearance is mediated by phenotypically distinct T cell response and that these features are present in patients with spontaneous viral clearance, in patients who successfully eradicate the virus after antiviral therapy and in resistant individuals who remain uninfected despite recurrent high risk exposures. Furthermore, the role of virus sequence heterogeneity in modifying this process is examined. The four hypotheses being tested in this application are as follows: First, HCV clearance is mediated by phenotypically distinct Thl/Tcl type T cell responses; Second, HCV clearance during antiviral therapy is mediated by a switch in the phenotype of virus-specific T cell response; Third, viral epitope sequence variations modify HCV-specific CTL response; Fourth, protective cellular immunity to HCV is present in individuals who remain uninfected despite frequent exposure. It is hoped that a better understanding of the cellular immune response during successful viral clearance would lead to development of strategies to eliminate chronic HCV infection and prevent its long term sequelae.